Cardiac output is defined as the volume of blood circulated per minute. It is equal to the heart rate multiplied by the stroke volume (the amount ejected by the heart with each contraction). Cardiac output averages approximately 5 liters per minute for an average adult at rest, although it may reach up to 30 liters/minute during extreme exercise.
Cardiac output is of central importance in the monitoring of cardiovascular health, as discussed by Conway “Clinical assessment of cardiac output”, Eur. Heart J. 11, 148-150 (1990). Accurate clinical assessment of the circulatory status is particular desirable in critically ill patients in the ICU and patients undergoing cardiac, thoracic, or vascular interventions, and has proven valuable in long term follow-up of outpatient therapies. As the patient's hemodynamic status may change rapidly, continuous monitoring of cardiac output will provide information allowing rapid adjustment of therapy. Measurements of cardiac output and blood pressure can also be used to calculate peripheral resistance.
A recent review of the various techniques for measuring cardiac output is given in Linton and Gilon, “Advances in non-invasive cardiac output monitoring”, Annals of Cardiac Anaesthesia, 2002, volume 5, p 141-148. This article lists both non/minimally invasive and invasive methods and compares the advantages and disadvantages of each.
The pulmonary artery catheter (PAC) thermodilution method is generally accepted as the clinical standard for monitoring cardiac output, to which all other methods are compared as discussed by Conway and Lund-Johansen (“Thermodilution method for measuring cardiac output”, Europ. Heart J. 11(Suppl 1), 17-20 (1990)). The long history of use has defined the technology, suitable clinical applications, and its inadequacies. Many new methods have attempted to replace the thermodilution technique, but none have so far gained acceptance.
Jansen (J. R. C. Jansen, “Novel methods of invasive/non-invasive cardiac output monitoring”, Abstracts of the 7th annual meeting of the European Society for Intravenous Anesthesia, Lisbon 2004) describes eight desirable characteristics for cardiac output monitoring techniques; accuracy, reproducibility or precision, fast response time, operator independency, ease of use, continuous use, cost effectiveness, and no increased mortality and morbidity. A brief description of some of these techniques follows.
Indicator dilution techniques. There are several indicator dilution techniques including transpulmonary thermodilution (also known as PiCCO technology, from Pulsion Medical Technologies of Munich, Germany), transpulmonary lithium dilution method (LiDCO Group plc of London, UK), PAC based thermodilution and other methods (Vigilance, Baxter; Opti-Q, Abbott; and TruCCOMS, AorTech). U.S. Pat. No. 6,757,544 to Rubinstein et al. teaches the technique of optically monitoring indicator dilution in a non-invasive manner for the purpose of computation of cardiac output, cardiac index, and blood volume. Transpulmonary indicator dilution methods with bolus injections are variations on the conventional bolus thermodilution method. CO is calculated with use of the Steward-Hamilton equation (Geddes, “Cardiac output using the saline dilution impedance technique”, IEEE Engineering in Medicine and Biology magazine March 1989, 22-26). Application of this equation assumes three major conditions; complete mixing of blood and indicator, no loss of indicator between place of injection and place of detection, and constant blood flow. The errors associated with indicator dilution techniques are primarily related to the violation of these conditions, as discussed by Lund-Johansen (“The dye dilution method for measurement of cardiac output”, Europ. Heart J. 11 (Suppl 1), 6-12 (1990)) and de Leeuw and Birkenhager (“Some comments of the usefulness of measuring cardiac output by dye dilution”, Europ. Heart J. 11 (Suppl 1), 13-16 (1990)). Of the mentioned methods the transpulmonary indicator dilution methods as well as the so-called ‘continuous cardiac output’ thermodilution methods have been partially accepted in clinical practice as described in, for example, Rödig et al. “Continuous cardiac output measurement: pulse contour versus thermodilution technique in cardiac surgical patients”. Br J Anaesth 1999; 50: 525.
Fick principle. The direct oxygen Fick approach is currently the standard reference technique for cardiac output measurement, as discussed by Keinanen et al., “Continuous measurement of cardiac output by the Fick principle: Clinical validation in intensive care”, Crit Care Med 20(3), 360-365 (1992), and Doi et al., “Frequently repeated Fick cardiac output measurements during anesthesia”, J. Clin. Monit. 6, 107-112 (1990). It is generally considered the most accurate method currently available, although there are many possibilities of introducing errors, and considerable care is needed. However when using the Fick method to trend cardiac output over a short time interval, i.e. during an operation or in an intensive care unit stay, many of these sources of errors are no longer pertinent. The NICO (Novametrix) system is a non-invasive device that applies Fick's principle on CO2 and relies solely on airway gas measurement as described by Botero et al., “Measurement of cardiac output before and after cardiopulmonary bypass: Comparison among aortic transit-time ultrasound, thermodilution, and noninvasive partial CO2 rebreathing”, J. Cardiothoracic. Vasc. Anesth. 18(5) 563-572 (2004). The method calculates effective lung perfusion, i.e. that part of the pulmonary capillary blood flow that has passed through the ventilated parts of the lung. The effects of unknown ventilation/perfusion inequality in patients may explain why the performance of this method shows a lack of agreement between thermodilution and CO2-rebreathing cardiac output as described in Nielsson et al. al “Lack of agreement between thermodilution and CO2-rebreathing cardiac output” Acta Anaesthesiol Scand 2001; 45:680.
Bio-Impedance and conduction techniques. The bio-impedance method was developed as a simple, low-cost method that gives information about the cardiovascular system and/or (de)-hydration status of the body in a non-invasive way. Over the years, a diversity of thoracic impedance measurement systems have also appeared. These systems determine CO on a beat-to-beat time base. Studies have been reported with mostly poor results, but in exceptional cases good correlations compared to a reference method. Many of these studies refer to the poor physical principles of the thoracic impedance method as described in Patterson “Fundamentals of impedance cardiography”, IEEE Engineering in Medicine and Biology 1989; 35 to explain the discrepancies. The accuracy of this technique is increased when the electrodes are placed directly in the left ventricle, rather than on the chest, however this also increases its invasiveness.
Echo-Doppler ultrasound. This technique uses ultrasound and the Doppler effect to measure cardiac output. The blood velocity through the aorta causes a ‘Doppler shift’ in the frequency of the returning ultrasound waves. Echo-Doppler probes positioned inside the esophagus with their echo window on the thoracic aorta may be used for measuring aortic flow velocity, as discussed by Schmidlin et al, “Transoesophageal echocardiography in cardiac and vascular surgery: implications and observer variability”, Brit. J. Anaesth. 86(4), 497-505 (2001). Aortic cross sectional area is assumed in devices such as the CardioQ, made by Deltex Medical PLC, Chichester, UK) or measured simultaneously as for example in the HemoSonic device made by Arrow International. With these minimally invasive techniques what is measured is aortic blood flow, not cardiac output. A fixed relationship between aortic blood flow and cardiac output is assumed. CO can therefore be calculated using this relationship. Abrupt changes in cardiac output are better followed with Doppler systems than with the PAC based continuous cardiac output systems as described in Roeck et al. “Change in stroke volume in response to fluid challenge: assessment using esophageal Doppler”, Intensive Care Med 2003; 29:1729. This measurement requires an above average level of skill on the part of the operator of the ultrasound machine to get accurate reliable results.
Arterial pulse contour analysis. The estimation of cardiac output based on pulse contour analysis is an indirect method, since cardiac output is not measured directly but is computed from a pressure pulsation on basis of a criterion or model. The origin of the pulse contour method for estimation of beat-to-beat stroke volume goes back to the Windkessel model as described in, for example, Manning et al. “Validity and reliability of diastolic pulse contour analysis (Windkessel model) in humans”, Hypertension. 2002 May; 39(5):963-8. Most pulse contour methods are based on this model explicitly or implicitly as described in Rauch et al. “Pulse contour analysis versus thermodilution in cardiac surgery”, Acta Anaesthesiol Scand 2002; 46:424, Linton et al. “Estimation of changes in cardiac output from arterial blood pressure waveform in the upper limb”, Br J Anaesth 2001; 86:486 and Jansen et al. “A comparison of cardiac output derived from the arterial pressure wave against thermodilution in cardiac surgery patients” Br J Anaesth 2001; 87:212.
Arterial pulse contour analysis techniques relate an arterial pressure or pressure difference to a flow or volume change. Three pulse contour methods are currently available; PiCCO (Pulsion), PulseCO (LiDCO) and Modelflow (TNO/BMI). All three of these pulse contour methods use an invasively measured arterial blood pressure and they need to be calibrated. PiCCO is calibrated by transpulmonary thermodilution, LiDCO by transpulmonary lithium dilution and Modelflow by the mean of 3 or 4 conventional thermodilution measurements equally spread over the ventilatory cycle. Output of these pulse contour systems is calculated on a beat-to-beat basis, but presentation of the data is typically within a 30-second window. A non-invasive pulse contour development is the combination of non-invasively measured arterial finger blood pressure with Modelflow as described in Hirschl et al. “Noninvasive assessment of cardiac output in critically ill patients by analysis of finger blood pressure waveform”, Crit Care Med 1997; 25:1909.
None of the above-mentioned CO techniques combines all of the eight “Jansen” criteria mentioned above. With respect to accuracy and precision, a number of methods may approach the thermodilution method with a precision of 15%. None of these new techniques has displaced conventional thermodilution based on the averaged result of 3 or 4 measurements done equally spread over the ventilatory cycle as described in Jansen et al. “An adequate strategy for the thermodilution technique in patients during mechanical ventilation”, Intensive Care Med 1990; 16:422. Under research conditions the use of this conventional thermodilution method remains the method of choice. However, in clinical settings, the lower precision of the continuous cardiac output techniques may be outweighed by their advantages of being automatic and continuous.
In addition to measuring cardiac output, it is also desirable in many critical care situations to continuously monitor a patient's blood oxygen level. Currently, hospitals routinely monitor blood oxygenation by pulse oximetry with a monitor attached to the patient's finger or earlobe as described for example in Silva et al., “Near-infrared transmittance pulse oximetry with laser diodes”, J. Biomed. Opt. 8(3), 525-533 (2003). Typically the oxygen monitor is a pair of light-emitting diodes (LED) and photodiodes on a probe clipped to a part of the patient's body. Red light from the LED reflects from the blood in a part of the patient's body, such as an ear-lobe or finger-tip. As a patient's oxygenation level drops, the blood becomes more blue, reflecting less red light to the photodiode. Such blood-oxygen monitors customarily measure percent of normal. Reassuring (normal) ranges are from 95 to 100 percent. For a patient breathing room air, at not far above sea level, an estimate of arterial oxygenation can be made from the blood-oxygen monitor reading. Unfortunately, measurements from such oxygen monitors cannot be reliably correlated to oxygenation in the patient's venous blood. Venous oxygen saturation is also a valuable parameter in the diagnosis of septic and cardiogenic shock as described below.
Other methods of measuring oxygenation: Diffuse optical tomography methods as described for example in Boas et al., Method for monitoring venous oxygen saturation”, US Patent application 20040122300 are conceptually appealing but are useful only where the vessels in the vicinity of the diffusing photon field are isolated veins. The presence of mixed arterial and venous blood complicates the problem to as described by Wolf et al., “Continuous noninvasive measurement of cerebral arterial and venous oxygen saturation at the bedside in mechanically ventilated neonates”, Crit. Care. Med 25(9), 1579-1582 (1997).
Ultrasound-tagged optical spectroscopy involves overlapping an ultrasound wave and a diffusing optical field, and modulating the frequency of the probe photons or their trajectories. A number of different technologies have been developed that utilize some interaction between ultrasound radiation and electromagnetic radiation. U.S. Pat. No. 5,212,667 to Tomlinson et al. and U.S. Pat. No. 5,174,298 to Dolfi et al. teach the technique of ultrasound tagged frequency-modulated imaging. Other patents teaching variations on the theme of frequency-modulated ultrasound tagging techniques include U.S. Pat. No. 6,815,694 to Sfez et al., U.S. Pat. No. 6,738,653 to Sfez et al., U.S. Pat. No. 6,041,248, to Wang, U.S. Pat. No. 6,002,958 to Godik, U.S. Pat. No. 5,951,481 to Evans, U.S. Pat. No. 5,293,873 to Fang. Trajectory modulation is detected by monitoring the speckle pattern of the photons emerging form the target. Image reconstruction techniques are then used to recreate a map of the path the photons followed in the medium. Imaging the speckle resulting from trajectory changes requires significant computation power and post-processing to yield an image. The technique has limited resolution, and is not yet capable of yielding functional (oxygenation) information in a fast flowing vessel.
Some variations of ultrasound-tagged frequency-modulated imaging rely on observing the frequency shift induced by the photoacoustic effect when an electromagnetic wave interacts in a medium with a sound wave. The electromagnetic wave (having a characteristic frequency ωOPT) receives a frequency shift at the ultrasound frequency ωUS to either the + or − side of the carrier wave ωOPT. Frequency modulation is detected by measuring the frequency shifted photons by for example using a Fabry-Perot etalon as described by Sakadzic and Wang, “High resolution ultrasound modulated optical tomography in biological tissues”, Opt. Lett. 29(23) 2004, p 2770-2772. Since the Doppler shifts induced by the ultrasound wave are very small compared to the probe photon carrier wave frequency, the detection system must be extremely sensitive to small frequency shifts. In addition, the frequency shift can be to both larger and smaller frequency of the initial carrier wave, and therefore some self-cancellation may result.